Method of pre-sensitizing cancer prior to treament with radiation and/or chemotherapy and a novel cytokine mixture

Abstract

This invention relates to a breakthrough method for pre-sensitizing cancer prior to a therapeutic treatment such as chemotherapy, radiation therapy or immuno-therapy and a novel cytokine mixture used in the method thereof. The cytokine mixture is a serum-free and mitogen-free mixture comprised of specific ratios of cytokines such as IL-1β, TNF-α, IFN-γ and GM-CSF to Interleukin 2 (IL-2), which is effective in inducing cancerous cells to enter a proliferative cell cycle phase thereby increasing their vulnerability to chemotherapy, radiation therapy and immuno-therapy. One such novel cytokine mixture is Leukocyte Interleukin Injection (LI) or Multikine®, which can be used alone or in combination with other drugs for the treatment of cancer thereby increasing the success of cancer treatment and the disease free survival of cancer patients.

1 . A method for pre-sensitizing cancer prior to a therapeutic treatment, comprising the step of: 
 administering a therapeutically active amount of a serum-free and mitogen-free cytokine mixture to cancer.    
     
     
         2 . The method of  claim 1 , wherein said therapeutic treatment is selected from the group consisting of chemotherapy, immuno-therapy and radiation therapy.  
     
     
         3 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally three times a week over a two week period in a range from about 20 IU to 1600 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         4 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally three times a week over a two week period in a range from about 40 IU to 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         5 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally three times a week over a two week period in a range from about 35 IU to 75 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         6 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally three times a week over a two week period at 55 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         7 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally three times a week over a two week period at 400 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         8 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally three times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         9 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered peritumorally five times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         10 . The method of  claim 1 , wherein half of said serum-free and mitogen-free cytokine mixture is administered peritumorally at a circumferential margin of the tumor mass and the other half of said mixture is administered at the submandibular lymphatic chain ipsylateral to the tumor mass three times a week over a two week period in a range from about 20 IU to 1600 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         11 . The method of  claim 1 , wherein half of said serum-free and mitogen-free cytokine mixture is administered peritumorally at a circumferential margin of the tumor mass and the other half of said mixture is administered at the submandibular lymphatic chain ipsylateral to the tumor mass three times a week over a two week period in a range from about 40 IU to 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         12 . The method of  claim 1 , wherein half of said serum-free and mitogen-free cytokine mixture is administered peritumorally at a circumferential margin of the tumor mass and the other half of said mixture is administered at the submandibular lymphatic chain ipsylateral to the tumor mass three times a week over a two week period at 400 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         13 . The method of  claim 1 , wherein half of said serum-free and mitogen-free cytokine mixture is administered peritumorally at a circumferential margin of the tumor mass and the other half of said mixture is administered at the submandibular lymphatic chain ipsylateral to the tumor mass three times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         14 . The method of  claim 1 , wherein half of said serum-free and mitogen-free cytokine mixture is administered peritumorally at a circumferential margin of the tumor mass and the other half of said mixture is administered at the submandibular lymphatic chain ipsylateral to the tumor mass five times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         15 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered perilymphatically three times a week over a two week period in a range from about 20 IU to 1600 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         16 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered perilymphatically three times a week over a two week period in a range from about 40 IU to 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         17 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered perilymphatically three times a week over a two week period at 400 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         18 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered perilymphatically three times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         19 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is administered perilymphatically five times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         20 . The method of  claim 1 , wherein said serum-free and mitogen-free cytokine mixture is comprised of specific ratios of cytokines selected from the group of IL-1β, TNF-α, IFN-γ and GM-C SF to Interleukin-2 (IL-2) as follows: 
 IL-1β to IL-2 at a ratio range of 0.4-1.5;    TNF-α to IL-2 at a ratio range of 3.2-10.9;    IFN-γ to IL-2 at a ratio range of 1.5-10.9; and    GM-CSF to IL-2 at a ratio range of 2.2-4.8.    
     
     
         21 . The method of  claim 20 , wherein said specific ratios of cytokines are as follows: 
 IL-1β to IL-2 at a ratio range of 0.6 to 0.8;    TNF-α to IL-2 at a ratio range of 7.7 to 11.3;    IFN-γ to IL-2 at a ratio range of 4.9 to 7.1; and    GM-CSF to IL-2 at a ratio range of 3.5 to 4.5.    
     
     
         22 . The method of  claim 1  wherein the serum-free and mitogen-free cytokine mixture is Multikine®.  
     
     
         23 . The method of  claim 1  wherein the serum-free and mitogen-free cytokine mixture is Leukocyte Interleukin Injection (LI).  
     
     
         24 . A method for inducing tumor cells into a cell cycle selected from the group of G 1 , S, G 2  and M, comprising the step of: 
 administering a therapeutically active amount of a serum-free and mitogen-free cytokine mixture to a cancerous cell.    
     
     
         25 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered three times a week over a two week period in a range from about 20 IU to 1600 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         26 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered three times a week over a two week period in a range from about 40 IU to 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         27 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered three times a week over a two week period in a range from about 35 IU to 75 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         28 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered three times a week over a two week period at 55 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         29 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered three times a week over a two week period at 400 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         30 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered three times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         31 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is peritumorally administered five times a week over a two week period at 800 IU wherein IU represent International Units for Interleukin-2 given in World Health Organization 1 st  International Standard for Human IL-2, 86/504.  
     
     
         32 . The method of  claim 24 , wherein said serum-free and mitogen-free cytokine mixture is comprised of specific ratios of cytokines selected from the group of IL-1β, TNF-α, IFN-γ and GM-CSF to Interleukin-2 (IL-2) as follows: 
 IL-1β to IL-2 at a ratio range of 0.4-1.5;    TNF-α to IL-2 at a ratio range of 3.2-10.9;    IFN-γ to IL-2 at a ratio range of 1.5-10.9; and    GM-CSF to IL-2 at a ratio range of 2.2-4.8.    
     
     
         33 . The method of  claim 32 , wherein said specific ratios of cytokines are as follows: 
 IL-1β to IL-2 at a ratio range of 0.6 to 0.8;    TNF-α to IL-2 at a ratio range of 7.7 to 11.3;    IFN-γ to IL-2 at a ratio range of 4.9 to 7.1; and    GM-CSF to IL-2 at a ratio range of 3.5 to 4.5.    
     
     
         34 . The method of  claim 24  wherein the serum-free and mitogen-free cytokine mixture is Multikine®.  
     
     
         35 . The method of  claim 24  wherein the serum-free and mitogen-free cytokine mixture is Leukocyte Interleukin Injection.  
     
     
         36 . A serum-free and mitogen-free cytokine mixture, comprising specific ratios of cytokines selected from the group of IL-1β, TNF-α, IFN-γ and GM-CSF to Interleukin-2 (IL-2) as follows: 
 IL-1β to IL-2 at a ratio range of 0.4-1.5;    TNF-α to IL-2 at a ratio range of 3.2-10.9;    IFN-γ to IL-2 at a ratio range of 1.5-10.9; and    GM-CSF to IL-2 at a ratio range of 2.2-4.8.    
     
     
         37 . The serum-free and mitogen-free cytokine mixture of  claim 36 , wherein said specific ratios of cytokines are as follows: 
 IL-1β to IL-2 at a ratio range of 0.6 to 0.8;    TNF-α to IL-2 at a ratio range of 7.7 to 11.3;    IFN-γ to IL-2 at a ratio range of 4.9 to 7.1; and    GM-CSF to IL-2 at a ratio range of 3.5 to 4.5.    
     
     
         38 . A pharmaceutical composition for use in treating cancer, comprising specific ratios of cytokines selected from the group of IL-1β, TNF-α, IFN-γ and GM-CSF to Interleukin-2 (IL-2) as follows: 
 IL-1β to IL-2 at a ratio range of 0.4-1.5;    TNF-α to IL-2 at a ratio range of 3.2-10.9;    IFN-γ to IL-2 at a ratio range of 1.5-10.9;    GM-CSF to IL-2 at a ratio range of 2.2-4.8, and optionally in combination with a pharmaceutically acceptable excipient, carrier or additive.    
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein said specific ratios of cytokines are as follows: 
 IL-1β to IL-2 at a ratio range of 0.6 to 0.8;    TNF-α to IL-2 at a ratio range of 7.7 to 11.3;    IFN-γ to IL-2 at a ratio range of 4.9 to 7.1; and    GM-CSF to IL-2 at a ratio range of 3.5 to 4.5.    
     
     
         40 . The pharmaceutical composition of  claim 39 , further comprising an IL-3 to IL-2 ratio in a range from 0.38-0.68, preferably at 0.53+/−0.15  
     
     
         41 . The pharmaceutical composition of  claim 39 , further comprising an IL-6 to IL-2 ratio in a range from 37.2-53.8, preferably at 46+/−5.9.  
     
     
         42 . The pharmaceutical composition of  claim 39 , further comprising an IL-8 to IL-2 ratio in a range from 261-561.5, preferably at 411+/−10.6.  
     
     
         43 . The pharmaceutical composition of  claim 39 , further comprising an IL-1α to IL-2 ratio in a range from 0.56-0.94, preferably at 0.75+/−0.19.  
     
     
         44 . The pharmaceutical composition of  claim 39 , further comprising an IL-10 to IL-2 ratio in a range from 2.82-3.22, preferably at 3.0+/−0.18.  
     
     
         45 . The pharmaceutical composition of  claim 39 , further comprising an IL-16 to IL-2 ratio in a range from 1.16-2.84, preferably at 1.84+/−0.68.  
     
     
         46 . The pharmaceutical composition of  claim 39 , further comprising a G-CSF to IL-2 ratio in a range from 2.16-3.78, preferably at 2.97+/−0.81.  
     
     
         47 . The pharmaceutical composition of  claim 39 , further comprising a TNF-β to IL-2 ratio in a range from 1.17-2.43, preferably at 1.8+/−0.63.  
     
     
         48 . The pharmaceutical composition of  claim 39 , further comprising a MIP-1α to IL-2 ratio in a range from 15.7-37.16, preferably at 22.7+/−7.0.  
     
     
         49 . The pharmaceutical composition of  claim 39 , further comprising a MIP-10 to IL-2 ratio in a range from 17.1-28.5, preferably at 22.8+/−5.7.  
     
     
         50 . The pharmaceutical composition of  claim 39 , further comprising a RANTES to IL-2 ratio in a range from 2.3-2.7, preferably at 2.5+/−0.13.  
     
     
         51 . The pharmaceutical composition of  claim 39 , further comprising a EGF to IL-2 ratio in a range from 0.267-0.283, preferably at 0.275+/−0.008.  
     
     
         52 . The pharmaceutical composition of  claim 39 , further comprising a PGE 2  to IL-2 ratio in a range from 3.63-5.42, preferably at 4.5+/−0.87.  
     
     
         53 . The pharmaceutical composition of  claim 39 , further comprising a TxB 2  to IL-2 ratio in a range from 23.47-25.13, preferably at 24.3+/−0.83.